Lithium salts continue to be the most promising drugs in the treatment of acute episodes and the prevention of relapses in patient suffering from manic depression or bipolar illness. Even though lithium salts have been used clinically in the treatment of bipolar patients for fifty years, their pharmacologic mode of action is unclear. The main goals of the research proposed in this applications are: (i) to advance the understanding at the molecular and cellular levels of the pharmacologic action of the Li+ ion in the treatment of bipolar disorder by analyzing the binding and transport properties of Li+, Mg2+ ions in human neuroblastoma and lymphoblatoma cells, and in purified wild-type and mutated guanine nucleotide-binding (G) proteins by using nuclear magnetic resonance (NMR) spectroscopy, and fluorescence spectroscopy and imaging; and (ii) to test the application of these spectroscopic and imaging methods to the identification of bipolar patients who are likely to respond to lithium treatment or are most susceptible to experiencing lithium toxicity. The proposed spectroscopic and imaging methods will test two interrelated mechanisms of actions Li+: a cell membrane abnormality, and a competition mechanism between Li+ and Mg2+ ions for membrane binding sites (in particular, anionic phospholipids and the metal-binding domain of G proteins). Our preliminary studies with cultured cells and G proteins indicate that the spectroscopic and imaging methods proposed in this study provide new information on Li+ interactions with cell components; this new information could not have been obtained with other techniques routinely used for Li+ analysis. In addition to contributing to an advancement of the understanding at the molecular and cellular levels of the pharmacologic action of the Li+ ion in the treatment of bipolar illness, the results of this study may also be useful in the diagnosis and prognosis of bipolar patients. More precisely defined molecular parameters, such as Li+ binding constants to the lymphoblastoma membranes from bipolar patients and their phospholipid composition, may by useful for predicting the success of Li+ therapy and the likelihood of Li+ toxicity.